AB0094 ANALYSIS OF CUMULATIVE DOSES OF METHOTREXATE IN THE HEPATIC DISEASE RISKTHROUGH IN VIVO AND IN VITRO APPROACHES IN PSORIATIC ARTHRITIS
Authors: M. Ruiz-Ponce, I. Arias de la Rosa, L. Cuesta López, C. Perez-Sanchez, C. López-Medina, M. D. López Montilla, M. C. Ábalos-Aguilera, P. Ortiz Buitrago, P. Navarro-Sanchez, A. Lucendo-Villarin, C. Lopez-Pedrera, A. Escudero Contreras, E. Collantes Estevez, N. Barbarroja Puerto
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Liver abnormalities, particularly non-alcoholic fatty liver disease (NAFLD) are strongly associated with psoriatic arthritis (PsA). In the last decades, the possible hepatotoxic effects of methotrexate in PsA have been studied, however, up to date, the results are controversial. <h3>Objectives</h3> 1) to evaluate the liver damage risk in PsA patients and its relationship with clinical features of the disease; 2) to determine the influence of cumulative doses of methotrexate by <i>in vivo</i> and <i>in vitro</i> approaches. <h3>Methods</h3> a cross-sectional study was performed on 326 subjects: 155 PsA patients, 87 NAFLD non-PsA patients, and 84 healthy donors (HDs). Clinical and laboratory parameters, liver disease biomarkers, and several indexes to evaluate the risk of suffering hepatic steatosis or fibrosis were evaluated. Cumulative doses of methotrexate were calculated retrospectively. Mechanistic studies were carried out on hepatocytes (HEPG2 cell line) treated with cumulative doses of methotrexate for up to 72 hours and 150µM. The changes in the levels of 92 inflammatory proteins on the hepatocytes were analyzed using PEA technology (Olink Target 96 Inflammation panel, Cobiomic Biosciences). <h3>Results</h3> using a NAFLD non-PsA BMI, age and sex-matched cohort, a cut-off value of hepatic steatosis index (HSI) (35.68; AUC=0.865 <i>p</i>&lt;0.0001) was calculated to distinguish NAFLD patients from HDs. Taking this value into account, PsA patients showed a significantly high risk of suffering NAFLD <i>vs</i> HDs, 65% respect to 22%. In addition, PsA patients with a high risk for steatosis displayed a significant prevalence of insulin resistance, obesity, type 2 diabetes mellitus, and arterial hypertension compared to PsA patients without that risk. Interestingly, these PsA patients also showed significantly elevated levels of triglycerides, complement component 3, DAPSA, c-reactive protein, and erythrocyte sedimentation rate. Next, PsA patients were divided into two groups depending on mean cumulative doses of methotrexate (&lt;1.5 gr for no hepatotoxic risk group and &gt;1.5 gr for the hepatotoxic risk group). Patients with more than 1.5gr of methotrexate cumulative dose showed significantly lower levels of acute phase reactants and no significant differences in metabolic profile or liver disease biomarkers. However, fibrosis-4 score (FIB-4) was significantly elevated in the group of hepatotoxic risk and positively correlated with cumulative doses. Although, this association was influenced by the age variable and not due to the levels of transaminases or platelets. On the other hand, <i>in vitro</i> treatment of hepatocytes with methotrexate for 24 h induced the expression of 19 inflammatory proteins out of 92. These changes were not significantly altered after 72 hours of treatment with methotrexate added each 24h. <h3>Conclusion</h3> 1) PsA patients with a high risk of liver disease show elevated rates of cardiometabolic comorbidities, inflammatory clinical markers and disease activity suggesting the link between metabolic alterations and the clinical features of PsA with the development of NAFLD, 2) PsA patients with high cumulative doses of methotrexate had no alteration of hepatic enzymes and indexes and 3) High cumulative doses of methotrexate <i>in vitro</i> did not show a significant impact on hepatocyte cells compared to low doses. Funded by ISCIII (PI20/00079 and RICOR-RD21/0002/0033), the Andalusian government (1381035-F) co-financed by ERDF. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.